A national cross-sectional survey of constipation in patients attending cancer centres in Ireland

Background: The prevalence of constipation in patients with cancer is estimated at 50-90%. It is often associated with pain, anorexia, nausea and vomiting and impacts negatively on quality of life. Despite its common occurrence, it is often poorly recognised and treated by healthcare professionals. Methods: A national cross-sectional survey was conducted in Ireland to describe constipation prevalence and severity in patients attending cancer centres and to evaluate management efficacy. In-patients or patients attending day oncology wards in any of the country’s eight designated cancer centres were eligible to participate. Participants were shown the Bristol Stool Chart and answered questions regarding stool appearance and sensation of incomplete defecation; they completed the Constipation Assessment Scale. Data on pain character and intensity, opioid use, and prescribed and over-the-counter laxative use were collected. Data were summarised using descriptive statistics. Significance of variations for continuous data were determined using t-tests. Conditional ordered logistic regression was undertaken to determine factors associated with constipation. Results: The dataset comprised 491 patients. 24.8% had been reviewed by specialist palliative care; 14.5% by the anaesthetic pain team. In total, 42.2% of respondents were taking step 2 or step 3 opioids. Constipation prevalence was 67.6%; 19.4% of patients had Constipation Assessment Scale scores indicating severe constipation. A total of 46% of the respondents were not taking any laxatives. Of those who were taking laxatives, 54.8% reported constipation symptoms. While opioid use was strongly associated with participants reporting higher scores, this association was not seen in those patients receiving specialist palliative care. Conclusions: Constipation remains a clinical problem in Irish cancer centres. Despite increased opioid use, patients receiving specialist palliative care were more likely to take laxatives and reported less constipation. Specialist palliative care practice should be studied in order to identify what are the transferable ‘ingredients’ of effective constipation management.


Introduction
Ireland has well-developed cancer and palliative care services and there is a growing focus on evidence-based practice and the development of learning healthcare systems 1 . National clinical guidelines have been published to support evidence-based practice and to improve the quality of care provided to patients. The management of cancer-related constipation has emerged as an area for improvement because it is a common condition that impacts negatively on quality of life, yet remains poorly recognised and treated [2][3][4] . Depending on methodology and population studied, its prevalence is estimated at 32-87%, with the highest incidence being reported in patients receiving opioids. This is significantly higher than the average prevalence of constipation in adults which has been estimated at 16% 5 . Constipation can be associated with pain, anorexia, nausea and vomiting. It can contribute to the development of haemorrhoids, anal fissures, urinary retention, bowel obstruction and delirium 6,7 . Accordingly, a national clinical guideline focused on constipation management for patients receiving palliative care was published in 2015 8 .
Although the literature contains reports of quality improvement initiatives focused on constipation management, efforts to improve quality have shown inconsistent results. Large scale initiatives are recognised to be challenging, and so effort has been focused on describing approaches that may be used to improve outcomes 9,10 . A key first step in quality improvement is convincing stakeholders that there is a problem relevant to them that needs to be addressed 11 . In Ireland, clinical experience suggested that the national guidelines were not being implemented outside of the hospice setting because clinicians failed to recognise the magnitude of the problem. There is a paucity of national data on constipation burden or management efficacy. Therefore, this study was carried out to establish the prevalence of constipation in patients attending cancer centres and to assess the efficacy of treatment. Little is known of the extent of constipation burden experienced by patients with cancer in Ireland. Reliable information on management efficacy is lacking. The data will be of value as a source of comparative data given relative paucity of recent prevalence studies in cancer populations [12][13][14] . We hope to stimulate consideration of the factors associated with improved outcomes and re-double clinical practice efforts to reduce constipation burden. Pilot testing was initially carried out with a convenience sample of seven patients in one cancer centre. The pilot study provided a number of valuable logistical insights, such as providing an accurate estimation of time required to complete data collection, and how best to manage the distribution and storage of each of the three copies of the consent forms (patient, medical record and research team copies). Only minor changes to the data collection instrument were made, however. The term 'medical chart' was replaced with 'medical record' as the latter was better understood by participants and data collectors. Also, adopting the practice of Woolery et al., 15 statements using lay terminology were used as clarifying descriptors for each Constipation Assessment Scale (CAS) 16 item for any participants who did not understand the original CAS item.

Ethics statement
Subsequently, data collection was carried out on a single day in each centre. It had been intended to carry out the study in all centres on the same day but operational issues meant that data was collected in two hospitals one week later.
A wide range of clinicians (consultants, specialist registrars, clinical nurse specialists, Advanced Nurse Practitioners, Assistant Directors of Nursing and Nurse Tutors) acted as data collectors for the study. All data collectors completed mandatory pre-study training comprising an e-learning presentation

Amendments from Version 1
The manuscript has been edited according to reviewer commentary to ensure consistency of terminology and to improve narrative order and flow. Additional detail (including reference to relevant literature) has been provided on the study context and impact on individual patient and societal levels. Greater explanatory detail on data collection has been provided including description of study instruments, time of data collection and acknowledgment of trade-offs that play an integral part of decision-making about what data to collect. The discussion of potential limitations associated with methods has been expanded. Clarification has been provided that this is the first national survey of constipation in patients attending cancer centres in Ireland, and greater detail has been provided on other international studies in order to provide greater understanding of comparability and generalisability.
Any further responses from the reviewers can be found at the end of the article REVISED explaining how to follow the study protocol, carry out data collection and record data. A member of the research team was also present on the study day to oversee data collection and provide any additional support, as needed.
In-patients or patients attending day oncology wards were eligible to participate. Inclusion criteria were: (1) cancer diagnosis; (2) informed of diagnosis (3) aged ≥18 years; (4) English speaking. Exclusion criteria were: (1) surgery ≤24 hours prior to the study; (2) cognitive impairment or reduced level of consciousness; (3) patient deemed too unwell to participate by the clinician. The inclusion criteria and data collection methods were applied consistently across all study sites to reduce the potential for bias.

Data collection
Data collectors first liaised with clinical nurse managers of each ward in order to identify eligible patients and then approached the potential participant. The data collector provided both verbal and written information on the study to the patient and answered any questions that were asked. Following this, patients were invited to take part in the study on that day. Although a 'cooling off' period of one hour was offered, patients could waive that if desired.
Demographic details were collected (gender and age) and the Constipation Assessment Scale (CAS) 16 completed. The Constipation Assessment Scale (CAS) is an 8-item self-report tool designed to measure bowel function in adults. It consists of a 3-point summated rating scale (0 = no problem; 1 = some problem; 2 = severe problem). Responses generate a constipation severity score where mild constipation is indicated by a score between 1-4; moderate between 5-9; and severe between 10-16. Evidence of reliability was supported by good internal consistency (r = 0.7-0.78) and high test-retest coefficients (r = 0.98) in the original validation study and in subsequent studies 17,18 . The CAS takes patients about 2 minutes to complete and is formatted at a reading level for 10-11 year olds. It is therefore associated with minimal participant burden.
Respondents were shown the Bristol Stool Chart 19 and asked "Can you look at this scale and thinking of the last time you had your bowels open, which picture best resembles what it looked like?". The Bristol Stool Chart 20 is a visual equivalent to the Bristol Stool Form Scale 21 . The ordinal scale evaluates stool consistency and is a surrogate measure for gastrointestinal transit time. Loose or liquid stools occur when there is limited gastrointestinal water absorption and they are associated with rapid intestinal transit time; harder stools occur when there is slow intestinal transit time and excessive water absorption. Types 1 and 2 are abnormally hard stools, while Types 6 and 7 are abnormally loose stools. The scale is widely used in clinical practice and research. It has demonstrated substantial validity and reliability 22 . Concurrent validity as measured by comparison of classification with stool water was moderate (Spearman's rho = 0.491, P < 0.001).
Two questions were asked about medications: 'Are you currently taking medication prescribed by your doctor to manage your constipation?' and 'Are you currently taking medication that you purchased yourself to manage your constipation?' Participants were not asked to provide the medication names; however, common laxatives that patients can purchase without a prescription in Ireland include bisacodyl, lactulose, senokot, dulcolax, fybogel, and milk of magnesia. Details on diagnosis, treatment and analgesics were extracted from chart review (see Extended data for a copy of the survey instrument 23 ).

Analysis
Data were summarised using descriptive statistics. Significance of variations for continuous data were determined using t-tests.
1) Conditional ordered logistic regression was undertaken to determine factors associated with constipation. A categorical variable based on CAS scores was the dependent variable: no constipation (CAS score=0); mild constipation (CAS score 1-6) or severe constipation (CAS score 7-16). The independent variables were: • Age -categorised during data collection in accordance with requirements for ethical approval at study sites.
• Gender-collected as a binary variable at the time of data collection.
• Primary cancer site -grouped into nine categories according to site of origin • Currently receiving chemotherapy -binary variable.
• Currently using opioids -binary variable (Step 2 ['weak opioids'] or Step 3 ['strong opioids']) • Currently utilising specialist palliative care servicesbinary variable • Laxative use -categorised into 4 groups capturing observed utilisation patterns: no use; using over-the counter only; using prescription only; using a combination prescription and over-the-counter laxatives.
2) Random effects logistic regression was undertaken to examine factors associated with laxative use. The binary dependent variable was laxative use (yes if taking any type of laxative). The independent variables were: • Age, gender, receiving chemotherapy, receiving radiotherapy, utilising specialist palliative care services and opioid use -these were handled in the same manner as described above • Additionally, the CAS score total was included as a continuous variable.
Analyses were carried out using Stata 15 24 , and tests of statistical significance were at p⩽0.05. In both models, odds ratios (OR) and 95% confidence intervals (CI) were estimated for each  were attending Day Oncology or haematology services, with the remainder receiving inpatient care. The specialist palliative care team were providing care to 24.8%; 14.5% had input from the anaesthetic pain team. Pain was reported by 62.5% and Step 2 or 3 analgesics were being used by 42%. Patients who were receiving palliative care or pain team input were more likely to be taking 2 ('weak opioid') or step 3 ('strong opioid') analgesics than patients who were not receiving input (p<0.001).

Prevalence
The prevalence of constipation among all participants was 67.6%, based on CAS criteria of a score of ≥1. Only 8.3% of respondents reported no symptoms while 19.4% of respondents scored ≥7, indicating severe constipation.
independent variable. All cases with incomplete data for the CAS items were excluded from regression analysis. Number of missing cases are shown in all relevant tables (Table 3 and  Table 4).
Reporting was provided according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria 25 (see Extended data for a copy of the completed STROBE checklist 23 ).

Participants
In total, 491 patients were recruited (Table 1); 51.5% were female and 46.2% were aged ≥65 years. Haematological, breast and genitourinary cancers were the most common diagnoses. 44.6%

Frequency Percentage
Laxative use:

None Prescribed laxatives
Over-the-counter laxatives (self-medicating) Both prescribed and over-the-counter laxatives

Symptom burden
Most commonly reported symptoms according to CAS ratings were reduced bowel movements (44.8%), change in the amount of gas passed rectally (44.8%) and abdominal distension or bloating (43.4%). The symptoms affecting patients most severely were reduced bowel movements (14.7%), abdominal distension or bloating (12%) and rectal fullness or pressure (11.4%). Further detail is provided in Table 2.
Using the Bristol Stool Chart, 20.9% reported hard stools, 55.2% reported normal stools and 17.6% reported loose stools. A weak negative correlation (r =-0.1), was observed for CAS scores and stool type, indicating that lower CAS scores were associated with looser stool.

Management
Just under half (46%) were not taking laxatives. 32.2% were taking prescribed laxatives. Some patients were self-medicating by taking over-the-counter laxatives-4.5% were taking over-the-counter laxatives alone, while a further 8.0% were taking both prescribed laxatives and supplementary over-the-counter laxatives. Despite taking laxatives, 54.8% of participants reported symptoms.

Factors associated with constipation burden
Ordered logistic regression analysis was conducted to examine factors associated with constipation (   .042) were also associated with increased odds of using laxatives.

Discussion
It has been observed that although there is a significant body of literature that examines the pharmacology of constipation management and best clinical practice, that the focus on cancer is limited and largely focused on opioid-induced constipation 26 . This study represents the first national survey of constipation attending cancer centres in Ireland and to our knowledge, worldwide. Study findings are notable in that significant constipation symptom burden is evident. The finding that 67.7% of participants were constipated echoes findings of high prevalence in specialist palliative care settings and in patients receiving opioids in Europe and the United States, 12-14 . Symptom profile was similar to the original CAS validation study 16 . Chronic constipation in the general population is more commonly seen in women 27 , and this association was also found in our study population. Opioid use, also unsurprisingly, was found to be most strongly associated with constipation in our study participants.
It has been observed that in recent years, there has been an increasing trend in self-medication with over-the-counter medications. Medications that are commonly available in Ireland and Europe without prescription include simple analgesics, vitamins and herbal remedies, cough remedies, anti-diarrhoeals and laxatives. Common over-the-counter laxatives in Ireland include bisacodyl, lactulose, senokot, dulcolax, fybogel, and milk of magnesia. Despite their availability, relatively little is known about use of non-prescription laxatives in Ireland. A survey that was conducted in Northern Ireland in 2005 found that 11.4% of participants reported regular stocking of over-the-counter laxatives 28 . Participants in this study demonstrate similar levels of use with 12.5% reporting use of non-prescription laxatives.
39.8% of participants were not taking laxatives despite symptoms, and 54.8% remained constipated despite taking laxatives. This points to a need not only to encourage appropriate laxative use but also to improve prescribing. Patients known to palliative care might be expected to be at higher risk of constipation due to opioid use and complex symptomatology. Importantly, an association between palliative care input and increased constipation burden was not observed. It is hypothesised that this is attributable to the fact that patients receiving palliative care benefitted from comprehensive symptom assessment and appropriate prescribing supported by guideline use. It points to the value of systematic constipation assessment in practice.
Different countries have taken different approaches to the development of constipation guidelines 29 . In Ireland, the only Acknowledging that misperceptions exist regarding the term 'palliative care' 30 , and noting the high prevalence of constipation found in the broader cancer population studied, it is possible that the title acted as a barrier to uptake. Planning is key to successful guideline development 31 , and identification of scope a critical first step 32 . While it is possible to develop broad guidelines, considerable resources are required and influence decisions regarding scope. Given the lack of improvement seen to date, we suggest that a broader approach in future guidelines should be considered to reduce fragmentation of practice and build momentum in quality improvement.
Study limitations include the fact that patient experience outside cancer centres is not described. While the multi-site design adds to the robust nature of data collection, logistical challenges meant that the study was not carried out on a single day and centres demonstrated variability in recruitment. Data collection was conducted in 2017 and it would be informative if the study were repeated and comparative data obtained for analysis. Practical lessons learned from this study should benefit any planned national survey-for example, selection of data items for collection necessitated efforts to balance comprehensiveness of data collection against burden to study participants who were attending hospital for cancer treatment. The experience of completing the survey tool was that it was short and user-friendly, and this allows for the possibility of collecting a limited amount of additional data in future surveys. A further limitation of this study is that data on refusal rate was not collected. The study was conducted at a time of changing data protection laws in Ireland and gatekeeper concerns regarding the requirement for explicit consent for data processing resulted in restrictions on data collection being applied. Finally, given the disparity of a single agreed definition for constipation, a potential confounder is chronic constipation as defined by ROME Diagnostic Criteria 33 . Future studies should aim to characterise patients who have a pre-morbid diagnosis of chronic constipation.

Conclusion
Cancer-related constipation remains inadequately recognised and treated in Ireland. The merits of symptom assessment and guideline application as evidenced by lower symptom burden associated with palliative care input are suggested. The confirmation of the high prevalence of constipation in the wider population, reaffirms the need to find more effective approaches to practice improvement across the cancer trajectory. Clinical guidelines are increasingly familiar part of clinical practice; they represent one option for improving the quality, safety and value of healthcare provision. This study highlights the need for further work to establish the efficacy of implementation of the management of constipation in Adult Patients Receiving Palliative Care guidelines. It provides a baseline against which progress can be tracked.

Data availability
Underlying data Due to the nature of this research and the consent document, participants of this study were not asked to consent to the sharing of data beyond the research team and their collaborators. As a result, underlying data cannot be publicly provided. Researchers seeking to access the underlying dataset will need to apply directly to all University 1.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes clearer. Abstract and introduction: It would be expected for the introduction to include what was said in the abstract background but to say it in more detail. For example, why are prevalence estimates so wide (50 to 90%). Also to set this in context what is the prevalence of constipation in the general population.